Abstract
The lack of antifungal drugs with novel modes of action reaching the clinic is a serious concern. Recently a novel antifungal protein referred to as Blad-containing oligomer (BCO) has received regulatory approval as an agricultural antifungal agent. Interestingly its spectrum of antifungal activity includes human pathogens such as Candida albicans, however, its mode of action has yet to be elucidated. Here we demonstrate that BCO exerts its antifungal activity through inhibition of metal ion homeostasis which results in apoptotic cell death in C. albicans. HIP HOP profiling in Saccharomyces cerevisiae using a panel of signature strains that are characteristic for common modes of action identified hypersensitivity in yeast lacking the iron-dependent transcription factor Aft1 suggesting restricted iron uptake as a mode of action. Furthermore, global transcriptome profiling in C. albicans also identified disruption of metal ion homeostasis as a potential mode of action. Experiments were carried out to assess the effect of divalent metal ions on the antifungal activity of BCO revealing that BCO activity is antagonized by metal ions such as Mn2+, Zn2+, and Fe2+. The transcriptome profile also implicated sterol synthesis as a possible secondary mode of action which was subsequently confirmed in sterol synthesis assays in C. albicans. Animal models for toxicity showed that BCO is generally well tolerated and presents a promising safety profile as a topical applied agent. Given its potent broad spectrum antifungal activity and novel multitarget mode of action, we propose BCO as a promising new antifungal agent for the topical treatment of fungal infections.
Highlights
Relative to antibacterial drug discovery, antifungal drug research has received less attention, (Delarze and Sanglard, 2015; Ngo et al, 2016); this is despite the fact that 1.2 billion people worldwide suffer from fungal diseases (Denning and Bromley, 2015) and mortality rates may exceed those caused by tuberculosis or malaria (Brown et al, 2012)
To analyze Blad-containing oligomer (BCO) genome-wide effects and to identify the mechanisms underlying its fungal growth inhibition (Pinheiro et al, 2016), RNA-seq was employed to analyze C. albicans transcriptome upon exposure to BCO for 4 h
The most up-to-date research for antifungal drug discovery is focused in alternative treatments with drugs aimed at novel fungal targets within the cellular circuitry crucial for stress response (Lamoth et al, 2014), drug resistance (Holmes et al, 2016), and virulence (Vila et al, 2017), the classical research for novel targets aimed at cell survival still prevails (Balouiri et al, 2016)
Summary
Relative to antibacterial drug discovery, antifungal drug research has received less attention, (Delarze and Sanglard, 2015; Ngo et al, 2016); this is despite the fact that 1.2 billion people worldwide suffer from fungal diseases (Denning and Bromley, 2015) and mortality rates may exceed those caused by tuberculosis or malaria (Brown et al, 2012). Most new promising compounds end up failing during the final development stages, mostly because of their mode of action (promoting fungal resistance) and/or toxicity issues This low success rate has definitely discouraged the pharmaceutical industry from investing their resources on this type of research and explains the absence of new drug classes since echinocandins were introduced in 2001. A novel class of antifungal drugs, named orotomides, is emerging, with very promising results in dimorphic and filamentous fungi, for Aspergillus spp., and is currently in late phase 1 clinical trials for the treatment of invasive aspergillosis (Oliver et al, 2016) It acts via a novel mechanism of action that targets a single enzyme (inhibition of the dihydroorotate dehydrogenase), and it has no activity against human pathogenic yeasts (Oliver et al, 2016). Drugs acting on a single cellular target are more likely to encounter the problem of drug resistance (Wong et al, 2014)
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